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Title: Molecular and cytogenetic analysis of premature ageing disease Hutchinson-Gilford Progeria Syndrome
Author: Seager, Anna L.
Awarding Body: University of Wales Swansea
Current Institution: Swansea University
Date of Award: 2006
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The principal aim of this study was to evaluate the underlying cellular mechanisms causing HGPS by using an in depth cytogenetic and molecular approach. Firstly, the total genome karyotype of HGPS lines and clinically normal cell lines was analysed utilising modified, multi-colour fluorescent in situ hybridisation (FISH), dual colour FISH, locus specific FISH, and DNA banding methods. The combinations of assays disclosed a characteristic cytogenetic mosaicsm in HGPS, with a distinctive pattern of complex, chromosome aberrations. In particular, chromosome 11 and X alterations were observed at a high frequency. This data suggested that HGPS displays features of chromosomal instability (CIN). There are several mechanisms which can lead to CIN; one such pathway includes disruption of the apparatus responsible for accurate chromosome division during mitosis. To assess the possibility that abnormalities in mitosis was involved in HGPS associated CIN, two different staining methods were employed to examine the spindles and centrosomes. These experiments were conclusive that mitotic spindle abnormalities were a mode of CIN induction in HGPS. In the second part of the study, the work was aimed at investigating the role of free radical damage in the HGPS premature ageing phenotype. Mitochondrial DNA is hypothesised to be particularly sensitive to the damaging effects of free radicals, and thus the levels mtDNA mutation were examined in HGPS relative to age – matched controls. The results showed that deletions were augmented in HGPS as compared to other children; a finding that was thought to reflect the inefficient antioxidant systems operating in HGPS fibroblasts.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available